Process For Producing A Solid Dispersion Of An Active Ingredient

ABSTRACT

A process for producing a solid dispersion of an active ingredient which comprises feeding the active ingredient and a matrix-forming agent to an extruder and forming a uniform extrudate, wherein the extruder comprises at least two rotating shafts ( 2 ), each of the shafts ( 2 ) carrying a plurality of processing elements disposed axially one behind the other, the processing elements defining (i) a feeding and conveying section (R; A), (ii) at least one reverse-flight section (D), and (iii) a discharging section (E), wherein the processing elements defining the reverse-flight section (R; D) comprise at least one reverse-flight element ( 14 ) which is based on a screw-type element having a conveying direction being opposite to the general conveying direction of the extruder.

RELATED APPLICATION DATA

This application is a continuation of U.S. application Ser. No.12/279,385, which is the U.S. national phase under 35 U.S.C. §371 ofInternational application Ser. No. PCT/EP2007/052315, filed Mar. 12,2007, designating the United States and published in English aspublication No. WO 2007/104748 A2 on Sep. 20, 2007 and claiming priorityto European patent application Ser. No. 06004999.6, filed Mar. 10, 2006,and U.S. provisional application Ser. No. 60/781,398, filed Mar. 10,2006. The entire disclosures of each of the aforementioned patentapplications are incorporated herein by this reference.

The present invention relates to a process for producing a soliddispersion of an active ingredient which comprises feeding the activeingredient and a matrix-forming agent to an extruder and forming auniform extrudate.

A continuous process for producing solid pharmaceutical forms, includingsolid solution products, has been known for some time and entailsconverting a melt of polymeric binder which contains active ingredientsinto the required drug form by injection molding or extrusion andsubsequent shaping (see, for example, EP-A-240 904, EP-A-240 906 andEP-A-337 256). Satisfactory results are obtained in this process whenthe active ingredient has a low melting point and/or a high solubilityin the molten polymeric binder. Active ingredients having a low meltingpoint are liquefied upon contact with the polymeric binder melt, and theliquefied active ingredient can be readily dispersed in the polymericbinder melt. Alternatively, active ingredients having a high solubilityin the molten polymeric binder readily dissolve in the polymeric bindermelt.

Problems occur when the active ingredient has a high melting pointand/or a limited solubility in the molten polymeric binder. Adequatedispersion of the active ingredient may require high temperatures of theextruder barrel, a relatively long mixing time and/or high shear inorder to bring about sufficient mixing of the active ingredient with thepolymeric binder melt. This may result in local overheating and damageto the product, especially when a shear- and temperature-sensitiveactive ingredient is being used. A further disadvantage of the necessityof high temperatures of the extruder barrel is high energy costs.

Furthermore, EP 0 580 860 B2 describes a process for producing a soliddispersion of a drug dissolved in a polymer, wherein a twin-screwextruder equipped with paddle means or kneading blocks is employed. Suchkneading blocks consist of, e.g. disk cams disposed offset in the mannerof a spiral staircase. The substance is pressed through a narrow taperedgap between the disk cams and the extruder housing. During the passagethrough the extruder, the material is thus subjected to high local shearforces, which may lead to excessive degradation of the active ingredientand/or the polymer. Shearing may also cause excessive wear of theextrusion equipment.

It is an object of the present invention to provide a process forproducing a solid dispersion of an active ingredient in a matrix-formingagent, in particular in a polymer, with improved mixing andhomogenization abilities. Furthermore, high temperatures or high localshear forces should be avoided.

It is another object of the present invention to provide a process forproducing a solid dispersion of an active ingredient in a matrix-formingagent, in particular in a polymer, in which degradation of the activeingredient and/or the matrix-forming agent and/or ancillary substancesis minimized.

The present invention provides a process for producing a soliddispersion of an active ingredient which comprises feeding the activeingredient and a matrix-forming agent to an extruder and forming auniform extrudate. The extruder comprises at least two rotating shafts,each of the shafts carrying a plurality of processing elements disposedaxially one behind the other. The processing elements define (i) afeeding and conveying section, (ii) at least one reverse-flight section,and (iii) a discharging section. The feeding and conveying section ispositioned farthest upstream, close to the hopper of the extruder, theat least one reverse-flight section is positioned downstream of thefeeding and conveying section, and the discharging section is positionedfarthest downstream, close to the discharge opening of the extruder. Theterm “downstream” as used herein, refers to direction in which thematerial is being conveyed in the extruder.

The processing elements may be formed separately. They may be strung,one behind the other, along the shaft of the extruder. However, it mayalso be possible that the processing elements are formed integrally. Inthis case, the surface structure of the element forms said processingelements.

According to the invention, the processing elements defining thereverse-flight section comprise at least one reverse-flight elementwhich is based on a screw-type element having a conveying directionopposite to the general conveying direction of the extruder. “Areverse-flight element which is based on a screw-type element” isintended to mean an element whose basic shape is that of a screwelement. Such an element differs from conventionally known kneadingelements or modified kneading elements. In particular, a kneadingelement allows an enhanced flow of the extrudate between its peripheryridges (i.e., its outer edge) and the barrel or bore of the extruder. Areverse-flight element which is based on a screw-type element accordingto the invention does only allow a small amount of the extrudate to flowbetween the edge of the screw and the barrel or bore of the extruder. Inan example of a conventional kneading element the clearings between theend of the element closest to the surface of the bore is greater thanthe clearance between the end of the reverse-flight elements accordingto the present invention closest to the surface of the bore.

The at least one reverse-flight element has a screw with areverse-flight relative to the screw-type elements which may be arrangedin the feeding and conveying section which define the general conveyingdirection of the extruder.

Furthermore, the reverse-flight element may preferably not have a planesurface area with a normal parallel and opposite to the generalconveying direction. In particular, the reverse-flight element may haveno face that is perpendicular to the general conveying direction.Therefore, it differs from kneading elements also with respect to theorientation of the surfaces. Moreover, the reverse-flight element doesnot have abutting faces that are perpendicular to the general conveyingdirection.

The reverse-flight element serves to create sufficient back-pressure toallow for a desired degree of mixing and/or homogenization. It isdesigned to stow the material conveyed in the extruder. Therefore it mayalso be called a back-pressure element. The reverse-flight element maybe derived from a reverse-flight screw, such that they convey thematerial in an opposite direction relative to the general conveyingdirection of the extruder. The reverse-flight elements may be formedseparately from other processing elements or integrally with otherprocessing elements.

Surprisingly, it has been found that the at least one reverse-flightelement enable a sufficient degree of mixing or homogenization.Furthermore, a relatively low temperature of the barrel of the extrudermay be chosen without deteriorating the quality of the extrudate.

According to an embodiment, the processing elements defining areverse-flight section comprise at least two reverse-flight elements andat least one positive-flight screw-type element which is arrangedbetween said two reverse-flight elements. In particular, the screw pitchof the reverse-flight elements is in a range from −0.5 times to −1.5times, preferably from −0.8 times to −1.2 times, the screw-pitch of thescrew-type elements of the feeding and conveying section and/or thescrew-type element(s) arranged between the two reverse-flight elements.Preferably, the screw-pitch of the reverse-flight elements is the sameas the screw pitch of the screw-type elements of the feeding andconveying section and/or the screw-type element(s) arranged between thetwo reverse-flight elements. Therefore, the difference between thescrew-type elements and the reverse-flight elements may only be thedirection of rotation of the screw.

The screw-type element(s) arranged between the two reverse-flightelements and the screw-type elements of the feeding and conveyingsection may be different. However, preferably, they are identical. Thereverse-flight elements may be identical to the screw-type elements notonly with respect to the absolute value of the screw pitch, but alsowith respect to the geometries of the surfaces that come into contactwith the extrudate.

According to an embodiment, the processing elements defining areverse-flight section comprise at least three reverse-flight elements,wherein at least one positive-flight screw-type element is arrangedbetween the respective successive reverse-flight elements. Therefore, inthe reverse-flight section, a reverse-flight element is followed by oneat least one positive-flight screw-type element which is followed by areverse-flight element which is again followed by at least onepositive-flight screw-type element which is followed by the thirdreverse-flight element. The length of the positive-flight screw-typeelement(s) arranged between the second and third reverse-flight elementsis in a range from 1 to 15 times, preferably from 1.5 times to 5 times,the length of the positive-flight screw-type element(s) arranged betweenthe first and second reverse-flight elements. Preferably, the length ofthe positive-flight screw-type element(s) arranged between the secondand third reverse-flight elements is twice that of the positive-flightscrew-type element(s) arranged between the second and thirdreverse-flight elements.

According to another embodiment, the processing elements defining thereverse-flight section comprise at least four reverse-flight elements,wherein at least one positive-flight screw-type element is arrangedbetween the respective successive reverse-flight elements, and whereinthe length of the positive-flight element(s) arranged between successivereverse-flight elements is the same.

In preferred embodiments, the processing elements additionally compriseat least one mixing element that is derived from a screw-type element.This at least one mixing element is arranged in the reverse-flightsection. The reverse-flight section comprising such a mixing element maytherefore also be called a mixing section. The mixing element(s)has/have preferably recesses formed in the screw flight of thescrew-type element.

A mixing element “being derived from a screw type element” is intendedto mean an element whose basic shape is that of a screw element, butwhich has been modified such that it exerts a compounding or mixingeffect in addition to a conveying effect. The underlying screw typeelement may have a positive-flight (positive-feed, “right-handed”) screwelement, may have a reverse-flight (negative-feed, “left-handed”) screwelement or a combination thereof. It is believed that the mode of mixingexerted by the mixing elements is predominantly distributive rather thandispersive mixing.

Until now, paddle means or kneading blocks have conventionally beenemployed in kneading and plasticizing pharmaceutical mixtures. Thesekneading blocks consist of cam disks mutually offset at an angle in aperipheral direction. The cam disks have abutting faces that areperpendicular to the general conveying direction in the extruder.Whereas these kneading blocks provide effective kneading andhomogenization, high local shear occurs at the edges of the cam disks.This local shear is believed to be detrimental to the active ingredientor other components.

The mixing elements used in accordance with the invention do not haveabutting faces that are perpendicular to the general conveyingdirection.

Preferred mixing elements do not have a plane surface area with a normalparallel and opposite to the general conveying direction. In particular,the mixing elements may have no face that is perpendicular to thegeneral conveying direction. Therefore, they differ from kneadingelements with respect to the orientation of the surfaces. However,mixing elements may allow an enhanced flow of the extrudate betweentheir periphery ridge (i.e., their outer edge) and/or said recesses andthe barrel or bore of the extruder.

Typically, the mixing element used in accordance with the invention hasrecesses formed in the screw flight of a screw type element. Mixingelements of this type are known as such and, for example, described inWO 2004/009326 A1, U.S. Pat. No. 5,318,358 and U.S. Pat. No. 6,106,142.

A preferred mixing element has a plurality of concentric ring portionsformed by grooves turned into a screw type element. Therefore, themixing element has a continuous screw flight, which is interrupted onlyby turned grooves with ring portions.

Surprisingly, it has been found that these mixing elements enable asufficient degree of mixing or homogenization with less degradation ofthe active ingredient or formation of other ingredients, compared to aconventional process employing paddle means or kneading blocks.Furthermore, a lower temperature of the barrel of the extruder may bechosen while still obtaining an extrudate of the same quality.Additionally, it has been found, surprisingly, that the inventive mixingelements provide a better self-cleaning effect. This self-cleaningeffect prevents that residues of the extruded material remain within theextruder over extended periods of time.

The extruder comprises at least two axis-parallel shafts and, inpreferred embodiments, is a twin-screw extruder. The shafts may beco-rotating or counter-rotating, but are preferably co-rotating. Theextruder may comprise more than two and, e.g., up to six shafts.Processing elements disposed on adjacent shafts closely intermesh.

The feeding and conveying section as well as the discharging sectionallow for a smooth passage of the material fed to the extruder from thefeed end to the discharge end of the extruder. The processing elementsemployed in the feeding and conveying section or the discharging sectionare typically in the form of an endless screw element, i.e. an elementcharacterized by an essentially continuous screw flight.

According to an advantageous aspect of the invention, the processingelements define [0029] (i) a feeding and conveying section, [0030] (ii)a first mixing section, positioned downstream of the feeding andconveying section, and [0031] (iii) an intermediate conveying section,positioned downstream of the first mixing section, [0032] (iv) areverse-flight section (second mixing section), positioned downstream ofthe intermediate conveying section, and [0033] (v) a dischargingsection, wherein the processing elements defining the first mixingsection comprise at least one mixing element and the processing elementsdefining the reverse-flight section comprise at least one mixing elementand downstream thereto at least one reverse-flight element.

The length of the feeding and conveying section is suitably selectedsuch that the material which is fed into the extruder has undergonesignificant softening or is nearly melting when the material enters thefirst mixing section or reverse-flight section if no mixing section isarranged upstream the reverse-flight section. Preferably, the feedingand conveying section corresponds to from about 20 to about 40% of theentire length of the shaft. Preferably, the discharging sectioncorresponds to from about 15 to about 30% of the entire length of theshaft.

In accordance with an advantageous aspect of the invention, a twin-screwextruder is used. It has at least two parallel co-rotating shafts. Inthe mixing section or in the mixing sections the shafts are equippedwith intermeshing mixing elements. The face of the mixing elements islimited by circular arcs corresponding to the outside screw diameter,the screw core diameter and at most the centre distance of the mixingelements. The shafts are guided on circular segments of the extruderhousing that are parallel to the shafts.

Advantageously, the mixing element comprises screw portions between thering portions which first cause a pressure buildup that forces thesubstance through the annular gap between the extruder housing and thering portions with shearing action and elongation; the pressure is thenreduced again. The recurring sequence of shear gap passage, pressurebuildup, shear gap passage, etc., on the mixing elements causes adefined stress on the substance and thus a uniform stress, withoutunduly stressing in particular the active ingredient.

The screw portions between the ring portions of a mixing element mayhave the same pitch flight. However, the pitch flight of these screwportions may also be different. According to an advantageous embodimentof the present invention, the screw portions of at least one mixingelement on each shaft have partly a positive screw flight and partly areverse-screw flight.

The annular and/or shear gap between the ring portions and the concavecircular segments of the extruder housing can have a different height toproduce a sufficient mixing effect for the active ingredient in thematrix-forming agent. For this purpose the ring portion might correspondonly to the core diameter of the screw shaft. The annular gap may alsohave a height of from 10 percent to 90 percent of the flight depth ofthe screw. Furthermore, the diameter of the ring portions may correspondapproximately to the center distance of two adjacent shafts.

Before the substance is stressed during its passage through the annularor shear gap, it must be transported a certain conveying distance by ascrew portion to build up the required pressure. For this purpose thescrew portions located between two adjacent ring portions generally havea length of at least 1/10, preferably at least ⅕, of the screw diameter.The turned grooves of the ring portions preferably have a depth of, forexample, ½ or less of the flight depth. The angle of the flanks of theturned grooves can be, for example, 30 to 90 degrees. Preferably,oblique grooves are turned, in particular at an angle of about 60degrees, to the shaft axis.

By stock removal on the screw crest and flanks, the mixing element canbe provided with further portions. Thus, in particular a mixing sectionwith substantially neutral conveying action can be provided by stockremoval.

After the annular gaps the screw flight can continue at the same pitchangle. That is, the screw portions of the mixing element can form acontinuous screw flight apart from the turned interruptions in the areaof the ring portions.

The ring portions permit additional dispersing surfaces to be gained. Asubstantial enlargement of the dispersing surface can moreover beobtained if the screw portions between the ring portions are disposed ata progressive angular offset from each other with the same direction ofrotation, for example, at an angular offset by half the flight angle.The angularly offset screw portions form faces angularly offset instep-like fashion as additional dispersing surfaces.

According to one embodiment of the invention the mixing element or themixing elements used on the shafts of the twin-screw extruder aredescribed in WO 2004/009326 A1, which is incorporated herein byreference. FIGS. 2 and 5 of WO 2004/009326 A1 show preferred mixingelements used in accordance with the invention. Further examples aredescribed below with reference to the accompanied drawings.

The solid dispersions manufactured by the process of the presentinvention contain one or more active ingredient and, optionally,additives. Additives may be used to impart desirable properties to thesolid dispersions or to facilitate the manufacture thereof. Although theactives and additives may be incorporated into the extruded mixture atany appropriate stage of the process, it may be preferred to introduce apart or all of the active ingredients or additives into the extruderseparately from the matrix-forming agent and/or other components.

Therefore, in an embodiment of the inventive process, at least part ofthe matrix-forming agent is fed to the hopper of the extruder and atleast one component selected from [0046] (i) the remainder of thematrix-forming agent, [0047] (ii) an active ingredient, [0048] (iii) anadditive, and [0049] (iv) combinations thereof, is introduced into theextruder through an opening in the extruder barrel at a positionupstream of or in a mixing section, or the reverse-flight section.

Preferably, the at least one component is introduced into the extruderat a position at or close to the junction of the feeding and conveyingsection and a mixing section or the reverse-flight section. Thecomponent may be solid, e.g. powdered, but preferably is liquid orliquefied.

Most preferably, the at least one component comprises a pharmaceuticallyacceptable surfactant.

The substances which are fed to the extruder are melted in order tohomogenize the melt and to disperse or dissolve the active ingredient inthe polymer efficiently.

“Melting” means transition into a liquid or rubbery state in which it ispossible for one component to be homogeneously embedded in the other.Melting usually involves heating above the softening point of thepolymer. Usually, the maximum melt temperature is in the range of 70 to250° C., preferably 80 to 180° C., most preferably 100 to 140° C.

The extruder housing is heated in order to form a melt from thesubstances fed to the extruder. It will be appreciated that the workingtemperatures will also be determined by the kind of extruder or the kindof configuration within the extruder that is used. A part of the energyneeded to melt, mix and dissolve the components in the extruder can beprovided by heating elements, while the friction and shearing of thematerial in the extruder can also provide the mixture with a substantialamount of energy and aid in the formation of a homogeneous melt of thecomponents.

In order to obtain a homogeneous distribution and a sufficient degree ofdispersion of the active ingredient, the active ingredient-containingmelt is kept in the heated barrel of the melt extruder for a sufficientlength of time.

According to a further aspect of the invention, the extruder barrelcomprises several heating zones. Preferably, the portion of the barrelupstream of the first mixing element or first reverse-flight element ismaintained at a lower temperature than the portion of the barreldownstream of the first mixing element or the first reverse-flightelement. It has been found that this temperature distribution leads to ahomogeneous, smooth and transparent extrudate which, in particular, hasnot been damaged by temperatures too high for the active ingredient.

In the extrudates produced according to the present invention, one ormore active ingredients are dispersed evenly throughout the polymer.This encompasses systems having small particles, typically of less than1 .mu.m in diameter, of active ingredient in the polymer phase. Thesesystems do not contain any significant amounts of active ingredients intheir crystalline or microcrystalline state, as evidenced by thermalanalysis (DSC) or X-ray diffraction analysis (WAXS). Typically, at least98% by weight of the total amount of active ingredients is present in anamorphous state.

When the extrudate is chemically and physically uniform or homogenousthroughout or consists of one phase (as defined by thermodynamics), thedispersion is called a “solid solution”. Solid solutions of activeingredients are preferred physical systems.

The polymer does not contain significant amounts of volatile solvents.The term “volatile solvent” is intended to encompass water and anycompound that is liquid at ambient temperature and has a highervolatility than water. Typically, the matrix contains less than 25%,preferably less than 6%, and most preferably less than 3% by weight of avolatile solvent.

Preferred extrudates formed by the process according to the inventioncomprise: [0061] from about 8 to 99.9% by weight (preferably 40 to 85%by weight, most preferably 50 to 70% by weight) of the matrix-formingagent (or any combination of such matrix-forming agents), [0062] fromabout 0.1 to 49% by weight (preferably 1 to 30% by weight) of an activeingredient or a combination of active ingredients, [0063] from 0 to 25%by weight (preferably 2 to 15% by weight) of at least onepharmaceutically acceptable surfactant, and [0064] from 0 to 25% byweight (preferably 0 to 15% by weight) of additives.

The matrix-forming agent may be any agent capable of setting or gellingfrom a liquified state, e.g. from a molten state, to form a continuousmatrix. Mixtures of matrix-forming agents can, of course, be used.

Useful matrix-forming agents are selected from polyols (i.e. sugaralcohols, sugar alcohol derivatives, or maltodextrines), waxes andlipids.

Suitable sugar alcohols include mannitol, sorbitol, xylitol; sugaralcohol derivatives include isomalt, or hydrogenated condensedpalatinose (as described in DE-A 10262005); further matrix-formingagents are maltodextrines.

Preferably, the matrix-forming agent includes a pharmaceuticallyacceptable polymer or a mixture of pharmaceutically acceptable polymers.Usually, pharmaceutically acceptable polymers are water-soluble or atleast water-dispersible.

Generally, the pharmaceutically acceptable polymer employed in theinvention has a Tg of at least about +10° C., preferably at least about+25° C., most preferably from about 40.degree. to 180° C. “Tg” meansglass transition temperature. Methods for determining the Tg values oforganic polymers are described in “Introduction to Physical PolymerScience”, 2nd Edition by L. H. Sperling, published by John Wiley & Sons,Inc., 1992. The Tg value can be calculated as the weighted sum of the Tgvalues for homopolymers derived from each of the individual monomers ithat make up the polymer, i.e. Tg=.SIGMA.W.sub.i X.sub.i where W is theweight percent of monomer i in the organic polymer and X is the Tg valuefor the homopolymer derived from monomer i. Tg values for thehomopolymers are indicated in “Polymer Handbook”, 2nd Edition by J.Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons,Inc., 1975.

Pharmaceutically acceptable polymers having a Tg as defined above allowthe preparation of solid dispersions that are mechanically stable and,within ordinary temperature ranges, sufficiently temperature stable sothat said solid dispersions may be used as dosage forms without furtherprocessing or can be compacted to tablets with only a small amount oftabletting aids. Dosage forms are, e.g., tablets, capsules, implants,films, foams, suppositories.

The pharmaceutically acceptable polymer comprised in the composition isa polymer that, when dissolved at 20° C. in an aqueous solution at 2%(w/v), preferably has an apparent viscosity of 1 to 50 000 mPa·s, morepreferably of 1 to 10 000 mPa·s, and most preferably of 5 to 100 mPa·s.For example, preferred pharmaceutically acceptable polymers can beselected from the group comprising:

homopolymers of N-vinyl lactams, especially polyvinylpyrrolidone (PVP),copolymers of a N-vinyl lactam and one or more comonomerscopolymerizable therewith, the comonomers being selected fromnitrogen-containing monomers and oxygen-containing monomers; especiallya copolymer of N-vinyl pyrrolidone and a vinyl carboxylate, preferredexamples being a copolymer of N-vinyl pyrrolidone and vinyl acetate or acopolymer of N-vinyl pyrrolidone and vinyl propionate;cellulose esters and cellulose ethers, in particular methylcellulose andethylcellulose, hydroxyalkylcelluloses, in particularhydroxypropylcellulose, hydroxyalkyl-alkylcelluloses, in particularhydroxypropylmethylcellulose, cellulose phthalates or succinates, inparticular cellulose acetate phthalate and hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose succinate orhydroxypropylmethylcellulose acetate succinate;polyvinyl alcohol-polyethylene glycol-graft copolymers (available asKollicoat® IR from BASF AG, Ludwigshafen, Germany);high molecular polyalkylene oxides such as polyethylene oxide andpolypropylene oxide and copolymers of ethylene oxide and propyleneoxide;polyacrylates and polymethacrylates such as methacrylic acid/ethylacrylate copolymers, methacrylic acid/methyl methacrylate copolymers,butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers,poly(hydroxyalkyl acrylates) and poly(hydroxyalkyl methacrylates),poly(ethylacrylate-methylmethacrylate-trimethyl-ammonioethylmethacrylate chloride);polyacrylamides;vinyl acetate polymers such as copolymers of vinyl acetate and crotonicacid, partially hydrolyzed polyvinyl acetate (also referred to aspartially saponified “polyvinyl alcohol”);polyvinyl alcohol;poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid),polylactide-co-glycolide, poly(3-hydroxybutyrate) andpoly(3-hydroxybutyrate-co-3-hydroxyvalerate); or mixtures of one or morethereof.

Among these, homopolymers or copolymers of N-vinyl pyrrolidone, inparticular a copolymer of N-vinyl pyrrolidone and vinyl acetate, arepreferred. A particularly preferred polymer is a copolymer of 60% byweight of the copolymer N-vinyl pyrrolidone and 40% by weight of thecopolymer vinyl acetate.

Hydroxypropylcellulose is another example of a particularly preferredpolymer.

Active ingredients used in the process according to the presentinvention are biologically active agents and include those which exert alocal physiological effect, as well as those which exert a systemiceffect, after oral administration. The invention is particularly usefulfor water-insoluble or poorly water-soluble (or “lipophilic”) compounds.Compounds are considered water-insoluble or poorly water-soluble whentheir solubility in water at 25° C. is less than 1 g/100 ml.

Examples of suitable active substances include, but are not limited to:

analgesic and anti-inflammatory drugs such as fentanyl, indomethacin,ibuprofen, naproxene, diclofenac, diclofenac sodium, fenoprofen,acetylsalicylic acid, ketoprofen, nabumetone, paracetamol, piroxicam,meloxicam, tramadol, and COX-2 inhibitors such as celecoxib androfecoxib;anti-arrhythmic drugs such as procainamide, quinidine and verapamil;antibacterial and antiprotozoal agents such as amoxicillin, ampicillin,benzathine penicillin, benzylpenicillin, cefaclor, cefadroxil,cefprozil, cefuroxime axetil, cephalexin, chloramphenicol, chloroquine,ciprofloxacin, clarithromycin, clavulanic acid, clindamycin,doxyxycline, erythromycin, flucloxacillin sodium, halofantrine,isoniazid, kanamycin sulphate, lincomycin, mefloquine, minocycline,nafcillin sodium, nalidixic acid, neomycin, nortloxacin, ofloxacin,oxacillin, phenoxymethyl-penicillin potassium, pyrimethamine-sulfadoximeand streptomycin;anti-coagulants such as warfarin;antidepressants such as amitriptyline, amoxapine, butriptyline,clomipramine, desipramine, dothiepin, doxepin, fluoxetine, reboxetine,amineptine, selegiline, gepirone, imipramine, lithium carbonate,mianserin, milnacipran, nortriptyline, paroxetine, sertraline and3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one;anti-diabetic drugs such as glibenclamide and metformin;anti-epileptic drugs such as carbamazepine, clonazepam, ethosuximide,gabapentin, lamotrigine, levetiracetam, phenobarbitone, phenyloin,primidone, tiagabine, topiramate, valpromide and vigabatrin;antifungal agents such as amphotericin, clotrimazole, econazole,fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole,miconazole nitrate, nystatin, terbinafine and voriconazole;antihistamines such as astemizole, cinnarizine, cyproheptadine,decarboethoxyloratadine, fexofenadine, flunarizine, levocabastine,loratadine, norastemizole, oxatomide, promethazine and terfenadine;anti-hypertensive drugs such as captopril, enalapril, ketanserin,lisinopril, minoxidil, prazosin, ramipril, reserpine, terazosin andtelmisartan;anti-muscarinic agents such as atropine sulphate and hyoscine;antineoplastic agents and antimetabolites such as platinum compounds,such as cisplatin and carboplatin; taxanes such as paclitaxel anddocetaxel; tecans such as camptothecin, irinotecan and topotecan; vincaalkaloids such as vinblastine, vindecine, vincristine and vinorelbine;nucleoside derivatives and folic acid antagonists such as5-fluorouracil, capecitabine, gemcitabine, mercaptopurine, thioguanine,cladribine and methotrexate; alkylating agents such as the nitrogenmustards, e.g. cyclophosphamide, chlorambucil, chiormethine,iphosphamide, melphalan, or the nitrosoureas, e.g. carmustine,lomustine, or other alkylating agents, e.g. busulphan, dacarbazine,procarbazine, thiotepa; antibiotics such as daunorubicin, doxorubicin,idarubicin, epirubicin, bleomycin, dactinomycin and mitomycin; HER 2antibodies such as trastuzumab; podophyllotoxin derivatives such asetoposide and teniposide; farnesyl transferase inhibitors; anthrachinonderivatives such as mitoxantron;anti-migraine drugs such as alniditan, naratriptan and sumatriptan;anti-Parkinsonian drugs such as bromocryptine mesylate, levodopa andselegiline;antipsychotic, hypnotic and sedating agents such as alprazolam,buspirone, chlordiazepoxide, chlorpromazine, clozapine, diazepam,flupenthixol, fluphenazine, flurazepam, 9-hydroxyrisperidone, lorazepam,mazapertine, olanzapine, oxazepam, pimozide, pipamperone, piracetam,promazine, risperidone, selfotel, seroquel, sertindole, sulpiride,temazepam, thiothixene, triazolam, trifluperidol, ziprasidone andzolpidem;anti-stroke agents such as lubeluzole, lubeluzole oxide, riluzole,aptiganel, eliprodil and remacemide;antitussives such as dextromethorphan and laevodropropizine;antivirals such as acyclovir, ganciclovir, loviride, tivirapine,zidovudine, lamivudine, zidovudine/lamivudine, didanosine, zalcitabine,stavudine, abacavir, lopinavir, amprenavir, nevirapine, efavirenz,delavirdine, indinavir, nelfinavir, ritonavir, saquinavir, adefovir andhydroxyurea;beta-adrenoceptor blocking agents such as atenolol, carvedilol,metoprolol, nebivolol and propanolol;cardiac inotropic agents such as aminone, digitoxin, digoxin andmilrinone;corticosteroids such as beclomethasone dipropionate, betamethasone,budesonide, dexamethasone, hydrocortisone, methylprednisolone,prednisolone, prednisone and triamcinolone;disinfectants such as chlorhexidine;diuretics such as acetazolamide, furosemide, hydrochlorothiazide andisosorbide;enzymes;essential oils such as anethole, anise oil, caraway, cardamom, cassiaoil, cineole, cinnamon oil, clove oil, coriander oil, dementholised mintoil, dill oil, eucalyptus oil, eugenol, ginger, lemon oil, mustard oil,neroli oil, nutmeg oil, orange oil, peppermint, sage, spearmint,terpineol and thyme;gastro-intestinal agents such as cimetidine, cisapride, clebopride,diphenoxylate, domperidone, famotidine, lansoprazole, loperamide,loperamide oxide, mesalazine, metoclopramide, mosapride, nizatidine,norcisapride, olsalazine, omeprazole, pantoprazole, perprazole,prucalopride, rabeprazole, ranitidine, ridogrel and sulphasalazine;haemostatics such as aminocaproic acid; lipid regulating agents such asatorvastatin, fenofibrate, fenofibric acid, lovastatin, pravastatin,probucol and simvastatin;local anaesthetics such as benzocaine and lignocaine;opioid analgesics such as buprenorphine, codeine, dextromoramide,dihydrocodeine, hydrocodone, oxycodone and morphine;parasympathomimetics and anti-dementia drugs such as AIT-082,eptastigmine, galanthamine, metrifonate, milameline, neostigmine,physostigmine, tacrine, donepezil, rivastigmine, sabcomeline,talsaclidine, xanomeline, memantine and lazabemide;peptides and proteins such as antibodies, becaplermin, cyclosporine,tacrolimus, erythropoietin, immunoglobulins and insuline;sex hormones such as oestrogens: conjugated oestrogens,ethinyloestradiol, mestranol, oestradiol, oestriol, oestrone;progestogens; chlormadinone acetate, cyproterone acetate, 17-deacetylnorgestimate, desogestrel, dienogest, dydrogesterone, ethynodioldiacetate, gestodene, 3-keto desogestrel, levonorgestrel, lynestrenol,medroxy-progesterone acetate, megestrol, norethindrone, norethindroneacetate, norethisterone, norethisterone acetate, norethynodrel,norgestimate, norgestrel, norgestrienone, progesterone and quingestanolacetate;stimulating agents such as sildenafil, vardenafil;vasodilators such as amlodipine, buflomedil, amyl nitrite, diltiazem,dipyridamole, glyceryl trinitrate, isosorbide dinitrate, lidoflazine,molsidomine, nicardipine, nifedipine, oxpentifylline and pentaerythritoltetranitrate;their N-oxides, their pharmaceutically acceptable acid or base additionsalts and their stereochemically isomeric forms.

Pharmaceutically acceptable acid addition salts comprise the acidaddition salt forms which can be obtained conveniently by treating thebase form of the active ingredient with appropriate organic andanorganic acids.

Active ingredients containing an acidic proton may be converted intotheir non-toxic metal or amine addition salt forms by treatment withappropriate organic and inorganic bases.

The term addition salt also comprises the hydrates and solvent additionforms which the active ingredients are able to form. Examples of suchforms are hydrates, alcoholates and the like.

The N-oxide forms of the active ingredients comprise those activeingredients in which one or several nitrogen atoms are oxidized to theso-called N-oxide.

The term “stereochemically isomeric forms” defines all possiblestereoisomeric forms which the active ingredients may possess. Inparticular, stereogenic centers may have the R- or S-configuration andactive ingredients containing one or more double bonds may have the E-or Z-configuration.

The term “pharmaceutically acceptable surfactant” as used herein refersto a pharmaceutically acceptable ionic or non-ionic surfactant.Incorporation of surfactants is especially preferred for matricescontaining poorly water-soluble active ingredients. The surfactant mayeffectuate an instantaneous emulsification of the active ingredientreleased from the dosage form and/or prevent precipitation of the activeingredient in the aqueous fluids of the gastrointestinal tract.

Preferred surfactants are selected from:

polyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether,polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers,e.g. polyoxyethylene (2) nonylphenyl ether,polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4) nonylphenylether or polyoxyethylene (3) octylphenyl ether;polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate orPEG-300 dioleate;alkylene glycol fatty acid mono esters, e.g. propylene glycolmonolaurate (Lauroglycol®); sucrose fatty acid esters, e.g. sucrosemonostearate, sucrose distearate, sucrose monolaurate or sucrosedilaurate;sorbitan fatty acid mono esters such as sorbitan mono laurate (Span®20), sorbitan monooleate, sorbitan monopalmitate (Span® 40), or sorbitanstearate,polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) orpolyoxyethyleneglycerol oxystearate such as polyethylenglycol 40hydrogenated castor oil (Cremophor® RH 40; BASF Corp.) orpolyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60; BASFCorp.); orblock copolymers of ethylene oxide and propylene oxide, also known aspolyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropyleneglycol such as Poloxamer® 124, Poloxamer® 188, Poloxamer®237, Poloxamer® 388, or Poloxamer® 407 (BASF Corp.); ormono fatty acid esters of polyoxyethylene (20) sorbitan, e.g.polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene(20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitanmonopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate(Tween® 20), or mixtures of one or more thereof.

Various additives may be included in the melt, for example flowregulators such as colloidal silica; lubricants, fillers, disintegrants,or plasticizers, stabilizers or preservatives.

Various other additives may be used, for example dyes such as azo dyes,organic or inorganic pigments such as iron oxides or titanium dioxide,or dyes of natural origin; stabilizers such as antioxidants, lightstabilizers, radical scavengers and stabilizers against microbialattack.

These additives may be incorporated into the mixture of activeingredient and polymer at any appropriate stage of the process. For easeof handling it is, however, convenient to include such additives in apowdery mixture of the matrix-forming agent and the active ingredientthat is being fed into the extruder.

The extrudate exiting from the extruder ranges from pasty to viscous.Before allowing the extrudate to solidify, the extrudate may be directlyshaped into virtually any desired shape. Shaping of the extrudate may beconveniently carried out by a calender with two counter-rotating rollerswith mutually matching depressions on their surface. A broad range oftablet forms can be attained by using rollers with different forms ofdepressions. If the rollers do not have depressions on their surface,films can be obtained. Alternatively, the extrudate is moulded into thedesired shape by injection-moulding. Alternatively, the extrudate issubjected to profile extrusion and cut into pieces, either before(hot-cut) or after solidification (cold-cut).

Additionally, foams can be formed if the extrudate contains a propellantsuch as a gas, e.g. carbon dioxide, or a volatile compound, e.g. a lowmolecular weight hydrocarbon, or a compound that is thermallydecomposable to a gas. The propellant is dissolved in the extrudateunder the relatively high pressure conditions within the extruder and,when the extrudate emerges from the extruder die, the pressure issuddenly released. Thus the solvability of the propellant is decreasedand/or the propellant vaporises so that a foam is formed.

Optionally, the resulting solid dispersion product is milled or groundto granules. The granules may then be compacted. Compacting means aprocess whereby a powder mass comprising the granules is condensed underhigh pressure in order to obtain a compact with low porosity, e.g. atablet. Compression of the powder mass is usually done in a tabletpress, more specifically in a steel die between two moving punches.

Preferably, at least one additive selected from flow regulators,disintegrants, bulking agents (fillers) and lubricants is used incompacting the granules. Disintegrants promote a rapid disintegration ofthe compact in the stomach and keep the granules which are liberatedseparate from one another. Suitable disintegrants are crosslinkedpolymers such as crosslinked polyvinyl pyrrolidone and crosslinkedsodium carboxymethylcellulose. Suitable bulking agents (also referred toas “fillers”) are selected from lactose, calcium hydrogenphosphate,microcrystalline cellulose (Avicel®), silicates, in particular siliciumdioxide, talc, potato or corn starch, and isomalt.

Suitable flow regulators are selected from highly dispersed silica(Aerosil®), and animal or vegetable fats or waxes.

A lubricant is preferably used in compacting the granules. Suitablelubricants are selected from polyethylene glycol (e.g., having a Mw offrom 1000 to 6000), magnesium and calcium stearates, sodium stearylfumarate, and the like.

The following examples will serve to further illustrate the inventionwithout limiting it.

FIG. 1 shows schematically a sectional view of the extruder that wasused for an example in accordance with the process according to thepresent invention;

FIG. 2 shows schematically a sectional view of an example of an extruderfor an embodiment of the process according to the present invention;

FIG. 3 shows schematically a sectional view of the extruder comprisingscrews comprising paddle means or kneading blocks that was used for anexample in accordance with the process according to the presentinvention;

FIG. 4 shows schematically a sectional view of the extruder that wasused for an example in accordance with the process according to thepresent invention;

FIG. 5 A and FIG. 5 B show one preferred embodiment of a mixing elementin accordance with the present invention;

FIG. 6 A and FIG. 6 B show another preferred embodiment of a mixingelement in accordance with the present invention; and

FIG. 7 A and FIG. 7 B show another preferred embodiment of a mixingelement in accordance with the present invention.

As the extruders shown in FIGS. 1 and 4 are generally similar, thegeneral arrangement of the extruder is described with reference to FIG.1.

The extruder is known per se. It has been used for producing a soliddispersion of an active ingredient in a matrix-forming agent. Theextruder comprises a housing or barrel 1 divided into several sectionsin a longitudinal direction. On the upstream side of the extruder, anopening 8 is provided for feeding a powder P of the active ingredientand the matrix-forming agent. Usually, a hopper is placed on thisopening so that the powder P can be easily fed into the barrel 1 of theextruder. In conveying direction X of the extruder, i.e. downstream fromthe opening 8, a further opening 9 for dosing a further component L,such as a surfactant, is provided. Here, the surfactant is pumped inliquid or liquefied form or dosed in solid form to the inside of barrel1. Even further downstream, another opening 10 is provided for suckinggas G from the inside of the barrel 1 to the outside of the barrel 1.The barrel 1 ends in conveying direction X in a die, where thedispersion is expelled.

Furthermore, the barrel 1 of the extruder is divided into three heatingzones H1, H2 and H3. The temperature of the barrel 1 in these heatingzones H1, H2 and H3 can be controlled in order to control the melting ofthe dispersion of the active ingredient and the matrix-forming agent.

Within the barrel 1 of the extruder, two parallel shafts 2 are arranged,one of which is shown in the sectional views of FIGS. 1 to 4.Preferably, the shafts 2 are co-rotating. The shafts 2 are equipped withprocessing elements disposed axially one behind the other. Theprocessing elements are arranged within the extruder barrel 1 so thatthe radially outermost portions of the processing elements are adjacentto the inner wall of the barrel 1. Only a very small gap is formedbetween the outermost portions of the processing element and the innerwall of the barrel 1. As FIGS. 1 to 4 are only schematic representationsto show the different zones of the extruder in a longitudinal direction,the shafts 2 with the processing elements and the extruder barrel 1 areshown apart from one another.

The shaft 2 with the processing elements is divided in several sections.In the following, these sections are described with respect to FIGS. 1to 4.

FIG. 1 shows an arrangement of processing elements for a firstembodiment of the process according to the present invention. Thesection furthermost upstream is a feeding and conveying section A. Theupstream side of this section A is adjacent to opening 8 for feedingpowder P into the barrel 1. On the downstream side of section A, theopening 9 of the barrel 1 is provided for feeding a surfactant to theinside of the barrel 1. The processing elements of the feeding andconveying section A are formed by screw-type elements 3, which form anendless screw having the feed direction X and a uniform pitch flight.Therefore, in section A, the powder P is fed into the extruder 1 andconveyed in the downstream direction X. The heating zones H1 and H2 ofthe extruder 1 are controlled so that the substances within the barrel 1start to melt at the end of the feeding and conveying section A.

Downstream from section A, a reverse-flight section R is arranged.Reverse-flight section R comprises reverse-flight elements 14-1, 14-2and 14-3. Between reverse-flight element 14-1 and reverse-flight element14-2, a screw-type element 3 is arranged having the same configurationas the screw-type elements 3 of the feeding and conveying section A.Between reverse-flight elements 14-2 and 14-3, two screw-type elements 3are arranged which are also identical to the screw-type elements 3 ofthe feeding and conveying section A. The length of the screw-typeelements 3 between the reverse-flight element 14-2 and 14-3 is twicethat of the screw-type element 3 between reverse-flight elements 14-1and 14-2. The geometry of the reverse-flight elements 14-1 to 14-3 isthe same as the geometry of screw-type elements 3 with the differencethat the screw-pitch has the opposite algebraic sign. However, the screwpitch of the reverse-flight elements 14-1 to 14-3 may also be in a rangefrom −0.5 times to −1.5 times, preferably from −0.8 times to −1.2 times,the screw-pitch of the screw-type elements 3 of the feeding andconveying section and/or the screw-type element(s) arranged between thetwo reverse-flight elements 14-1 to 14-3

Downstream of the reverse-flight section R, a discharge section E isarranged. The shaft 2 of the extruder in discharge section E is equippedwith screw-type elements 3, which are identical to the elements used insection A. In discharge section E the melt is only fed to the die of theextruder.

In practice a polymer and the matrix-forming agent are fed to the insideof barrel 1 of the extruder through opening 8. The matrix-forming agentand the active ingredient are conveyed by screw elements 3 toreverse-flight element 14-1. Heating zones H1 and H2 are heated to atemperature so that the polymer and the matrix-forming agent start tomelt just before mixing element 11. Here as well, surfactants are fedthrough opening 9 to the inside of the barrel 1. The melt then passesreverse-flight element 14-1 and is conveyed by the screw-type elementbetween reverse-flight elements 14-1 and 14-2 to the secondreverse-flight element 14-2. The melt then passes reverse-flight element14-2 and is conveyed by the screw-type elements between reverse-flightelements 14-2 and 14-3 to the third reverse-flight element 14-3. In thereverse-flight section R, the main mixing and melting effect isperformed. Thereafter, the uniform extrudate is conveyed by screwelements 3 of discharging section E to the die of the extruder.

FIG. 2 shows another arrangement of processing elements for a secondembodiment of the process according to the present invention.

The processing elements of sections A and E are the same as in thearrangement of processing elements shown in FIG. 1. However, section Amay be shorter than section A as shown in FIG. 1, as the reverse-flightsection R of the arrangement shown in FIG. 2 is longer than thereverse-flight section R of the arrangement shown in FIG. 1.

Downstream from section A, a reverse-flight section R is arranged. Thereverse-flight section R of this embodiment comprises a reverse-flightelement 14-1, followed by screw-type elements 3, which are identical tothe screw-type element 3 arranged between reverse-flight elements 14-1and 14-2 shown in FIG. 1. There follows a reverse-flight element 14-2,which is identical to reverse-flight element 14-1. Subsequently,screw-type elements 3 are arranged, which are identical to screw-typeelements 3 with respect to shape as well as to length, which arearranged between reverse-flight elements 14-1 and 14-2. Then, anotherreverse-flight element 14-3 is arranged, which is identical to the firsttwo reverse-flight elements 14-1 and 14-2. Subsequently, furtherscrew-type elements 3 are arranged, which are identical in shape andlength to the screw-type elements 3 arranged between reverse-flightelements 14-1 and 14-2 and between 14-2 and 14-3. Finally, areverse-flight element 14-4 is arranged at the end of reverse-flightsection R, which is identical to the preceding reverse-flight elements14-1 to 14-3.

The reverse-flight elements used in the arrangements shown in FIGS. 1and 2 are elements whose basic shape is that of a screw element. Such anelement differs from conventionally known kneading elements or modifiedkneading elements. In particular, a kneading element allows an enhancedflow of the extrudate between its periphery ridges (i.e., its outeredge) and the barrel or bore of the extruder. The reverse-flightelements which are based on a screw-type element according to theinvention do only allow a small amount of the extrudate to flow betweenthe edge of the screw and the barrel or bore of the extruder.

Furthermore, the reverse-flight elements have not a plane surface areawith a normal parallel and opposite to the general conveying direction.Moreover, the reverse-flight element does not have abutting faces thatare perpendicular to the general conveying direction.

With respect to FIG. 3, a further arrangement of processing elements fora third embodiment of the process according to the present invention isdescribed.

The processing elements of sections A and E are the same as in thearrangement of processing elements shown in FIG. 1. However, section Amay be shorter than section A as shown in FIG. 1.

Downstream from section A, a mixing section B is arranged. Theprocessing elements in mixing section B comprises so-called paddle meansor kneading blocks 4, which consist of disk cams. On the downstream sideof mixing section B, an intermediate conveying section C is formed. Theprocessing elements of intermediate section C are the same screw-typeelements 3 used in the feeding and conveying section A. Therefore,intermediate conveying section C only conveys the melt from mixingsection B to the next section.

Downstream of the intermediate conveying section C, a reverse-flight orsecond mixing section D is arranged. In section D the processingelements are paddle means or kneading blocks 5 and 6. On the downstreamside of kneading block 6, a reverse-flight element 7 is positioned. Thereverse-flight element 7 serves to create sufficient back-pressure toallow for a desired degree of mixing and/or homogenization. Itaccumulates the material into mixing sections B and D. Thereverse-flight element 7 is derived from a screw-type element having areverse-pitch flight, such that it conveys the melt in an oppositedirection relative to the general conveying direction X of the extruder.The reverse-flight element 7 is identical to reverse-flight elements 14shown in FIGS. 1 and 2.

It should be mentioned that the use of paddle means or kneading blocks 5and 6 is known per se. However, the use of a reverse-flight element 7 inconnection with the arrangement of the extruder shown in FIG. 3 is notknown per se.

Downstream from the second mixing section D, a discharging section E isarranged. The shaft 2 of the extruder 2 is equipped with screw-typeelements 3, which are identical to the elements used in sections A andC. In discharging section E, the melt is only fed to the die of theextruder.

With respect to FIG. 4, a further arrangement of processing elements fora forth embodiment of the process according to the present invention isdescribed.

The processing elements of sections A, C and E are the same as in thearrangement of processing elements shown in FIG. 3. The arrangement ofFIG. 4 differs from the arrangement of FIG. 3 in the processing elementsof sections B and D. In section B the shaft 2 of the extruder used inthe forth embodiment is equipped with a particular mixing element 11instead of the paddle means or kneading blocks 4 of section B of thethird embodiment. The mixing element is described in greater detailbelow with reference to FIGS. 5 to 7. Furthermore, in the second mixingsection D of the extruder of the forth embodiment, the shaft is equippedwith particular mixing elements 12, 13 instead of the paddle means orkneading blocks 5 and 6 of section D of the third embodiment. Mixingelements 12,13 are again described in greater detail below withreference to FIGS. 5 to 7. Mixing elements 12,13 may be identical tomixing element 11 of the first mixing section B. However, in theembodiment shown in FIG. 5, the mixing element is divided into portions12 and 13, portion 12 having a positive feeding direction and portion 13having a negative feeding direction or a reverse flight.

Downstream from mixing elements 12,13, a reverse-flight element 14 isarranged, which corresponds to the reverse-flight element 14-1 to 14-3and 7 described above.

It should be noted that the length of kneading blocks 4 corresponds tothe length of the mixing element 11 and the length of kneading blocks 5,6 corresponds to the length of mixing elements 12,13.

Downstream from the second mixing section D, a discharging section E isarranged. The shaft 2 of the extruder is equipped with screw-typeelements 3, which are identical to the elements used in sections A andC. In discharging section E, the melt is only fed to the die of theextruder.

In practice a polymer and the matrix-forming agent are fed to the insideof barrel 1 of the extruder through opening 8. The matrix-forming agentand the active ingredient are conveyed by screw elements 3 to mixingelement 11. Heating zones H1 and H2 are heated to a temperature so thatthe polymer and the matrix-forming agent start to melt just beforemixing element 11. Here as well, surfactants are fed through opening 9to the inside of the barrel 1. The melt then passes mixing element 11and is conveyed by screw elements 3 of the intermediate conveyingsection C to the second mixing section D comprising mixing elements12,13 and thereafter reverse-flight element 14. Here, the main mixingand melting effect is performed. Thereafter, the uniform extrudate isconveyed by screw elements 3 of discharging section E to the die of theextruder.

In the following, examples of mixing elements that may be used in mixingsections B and D are described with reference to FIGS. 5 to 7.

In general, the mixing elements 15, 20, and 24 shown in FIGS. 5 to 7 andwhich may be used as mixing elements 11 to 13 on the two shafts 2 have atransverse profile 23 composed of three circular arcs. One circular archas a diameter corresponding to the diameter of the outer screw, anothercircular arc has a diameter corresponding to the diameter of the screwcore, and a further circular arc has a diameter whose radius correspondsto the center distance of the two elements of the mixing element (cf.EP-B-0002 131).

Further, the mixing elements 15, 20, and 24 comprise a bore 22 havingprojections for engagement with grooves of the shaft 2 so that themixing elements 15, 20, and 24 can be rotated together with the shaft 2.

As can be seen from FIGS. 5A and 5B, the mixing element 15 has five ringportions 16 that are concentric with the shaft axis and disposed adistance apart from another. The ring portions 16 are obtained bygrooves turned into the mixing element 15. The angle of the flanks 18 ofthe grooves to the shaft axis is about 60 degrees. The height of theannular gaps 19 between the ring portions 16 and the inner wall of theextruder barrel 1 is about the flight depth, i.e. the difference betweenthe core diameter and the outside screw diameter. The diameter of thering portions 8 thus corresponds to the core diameter of the screw.

In mixing element 15 a continuous screw flight may be formed which isinterrupted only by the turned grooves with ring portions 16. Incontrast, screw portions of the mixing element 15 between ring portions16 may also be disposed at a progressive angular offset from each otherwith the same direction of rotation.

The screw sections 17 a, 17 b, 17 c, 17 d between the ring portion 16 ofmixing element 15 in the embodiment shown in FIGS. 5A and 5B have thesame screw pitch. The mixing element 15 shown in FIGS. 5A and 5B may beused in particular as mixing element 11 in mixing section B as shown inFIG. 5.

A further example of a mixing element 20 is shown in FIGS. 6A and 6B.Mixing element 20 differs from mixing element 15 in screw sections 21 a,21 b, 21 c, 21 d between ring portions 16. Screw sections 21 a and 21 bmay correspond to 17 a and 17 b of mixing element 15. However, screwsections 21 c and 21 d of mixing element 20 differ from screw sections17 c and 17 d of mixing element 15. Namely, screw sections 21 c and 21 dhave a reverse-flight screw so that these sections 21 c and 21 d conveythe melt in an opposite direction relative to the general conveyingdirection X of the extruder and the conveying direction of screwsections 21 a and 21 b.

Screw sections 21 a and 21 b may be formed integrally with screwsections 21 c and 21 d as shown in FIGS. 6A and 6B. However, two mixingelements may also be provided, one comprising screw sections 21 a and 21b and the other comprising screw sections 21 c and 21 d. Mixing element20 may correspond to mixing elements 12, 13 of the second mixing sectionD shown in FIG. 5.

A further example of a mixing element 24 is shown in FIGS. 7A and 7B. Asfor the screw sections 26 a, 26 b, 26 c and 26 d, the mixing element 24is similar to mixing element 20 shown in FIGS. 6A and 6B. Screw section26 a and 26 b have a positive screw flight and screw section 26 c and 26d have a negative screw flight or reverse-flight screw.

Furthermore, mixing element 24 differs from mixing elements 20 and 15 inthe annular gap 27 between the ring portions 25 and the extruder barrel1. In the example of mixing element 24, the height of the annular gaps27 is about half of the flight depth, i.e. half the difference betweenthe core diameter and the outside screw diameter. The diameter of thering portions 8 thus corresponds approximately to the center distance ofthe two shafts from each other. The larger diameter of ring portions 25relative to the diameter of ring portions 16 of mixing elements 20 and15 provides a barrier for the melt. It has been found that such abarrier is advantageous if the mixing element 24 is used as mixingelements 12, 13 in the second mixing section D as shown in FIG. 5. Thebarrier provides a compacting zone within the extruder in which thepressure of the extrudate is raised on the substance supply side.

The following provides examples in which the same solid dispersion of anactive ingredient in a polymer has been produced by, first, the extruderwith the screw arrangement shown in FIG. 3 as a comparative example and,second, the extruder with the screw arrangement shown in FIG. 5.

EXAMPLE 1

An extrudate was prepared from the ingredients given in Table 1.

TABLE 1 Compositions of Extrudates Formulation Ibuprofen 25 USP (active  40 wt % ingredient) Kollidon Typ CL (polymer)   5 wt % Povidon Typ K3023.8 wt % (polymer) Sodium carbonate   20 wt % Isomalt Typ PF 10.2 wt %Aerosil Typ 200 (glidant)  1.0 wt %

The active ingredients, the polymer and the glidant were thoroughlymixed and the resulting powder was fed into a twin-screw extruder(ZSK-40, manufactured by Werner & Pfleiderer, Germany). The screwconfiguration comprised reverse-flight elements in addition to conveyingelements and is shown in FIG. 1. During the extrusion process, powdermixture was melted. Vacuum was applied to the mixture in the last thirdof the extruder The process parameters are detailed in Table 2.Subsequent to the extrusion step, the material was formed on a calendarand cooled to reveal a band of lentil-shaped extrudate.

TABLE 2 Process Parameters Formulation Formulation Flow rate 17.0extruder [kg/h] Screw speed [rpm] 100 Vacuum [mbar] 150 Temperaturebarrel 1 [° C.] 25 barrel 2 + 3 [° C.] 80 barrel 4 − 6 [° C.] 130

The properties of the extrudate were acceptable which means that theextrudate could be shaped by calendaring.

EXAMPLE 2

An extrudate was prepared from the ingredients given in Table 3.

TABLE 3 Composition of extrudates Formulation 1 Formulation 2 Lopinavir(active 24.00% 23.49% ingredient) Ritonavir (active  6.00%  5.87%ingredient) Copovidone (polymer) 63.00% 61.66% Emulsifier mixture  6.0% 8.0% Aerosil 200 (glidant)  1.00%  0.98%

The active ingredients, the polymer and the glidant were thoroughlymixed and the resulting powder was fed into a twin-screw extruder(ZSK-40, manufactured by Werner & Pfleiderer, Germany). The screwconfiguration comprised kneading blocks in addition to conveyingelements and is shown in FIG. 3. The emulsifiers were fed into theextruder by means of a liquid dosing pump. The emulsifiers were added ata position immediately before the material in the extruder reaches thefirst kneading block section. During the extrusion process, the liquidemulsifiers were blended with the powder and the mixture was melted.Vacuum was applied to the mixture in the last third of the extruder. Theprocess parameters are detailed in Table 4. Subsequent to the extrusionstep, the material was formed on a calendar and cooled to reveal a bandof lentil-shaped extrudate.

TABLE 4 Process Parameters Formulation 1 Formulation 2 Feeding RatePowder [g/h] 15.7 15.7 liquid [g/h] 1.0 1.36 Screw speed [rpm] 100 120Vacuum [mbar] 350 200 Temperature barrel 1 [° C.] 20 20 barrel 2 + 3 [°C.] 80 80 barrel 4 − 6 [° C.] 100 100 die head [° C.] 125 125 die [° C.]125 125 Torque [% of engine power] 35 35 Appearance of extrudate Smooth,transparent Smooth, transparent Temperature of extrudate 125 127-128 [°C.]

Analytical test results for the extrudates are given in Table 5. Thelopinavir/ritonavir content and the content of a major ritonavirdegradation product were determined by HPLC. Water content wasdetermined by Karl-Fischer-Titration, and tests for crystallinity wereconducted by DSC.

TABLE 5 Analytical results of extrudates Formulation 1 Formulation 2Crystallinity None None Lopinavir 102.3% 101.5% Ritonavir  97.5%  97.0%Ritonavir degradation  0.28%  0.37% product Relative amount ritonavir0.287% 0.381% degradation product/ ritonavir Water content  1.1%  0.8%

EXAMPLE 3

Example 2 was repeated. However, the screws were designed differently:instead of kneading blocks, it comprised mixing elements. Theconfiguration of this screw is depicted in FIG. 4. The kneading blocksin screw ZSK 40-54 (FIG. 3) are replaced by mixing elements with bothmixing zones being equivalent in length. Mixing section B comprises amixing element 15 according to FIG. 5; mixing section D comprises amixing element 20 according to FIG. 6. The process parameters are givenin Table 6, the analytical results are given in Table 7.

TABLE 6 Process Parameters Formulation 1 Formulation 2 Feeding RatePowder [g/h] 15.7 15.7 liquid [g/h] 1.0 1.36 Screw speed [rpm] 100 120Vacuum [mbar] 350 200 Temperature barrel 1 [° C.] 20 20 barrel 2 + 3 [°C.] 80 80 barrel 4 − 6 [° C.] 100 100 die head 125 125 die [° C.] 125125 Torque 36 33 [% of engine power] Appearance of extrudate Smooth,transparent Smooth, transparent Temperature of extrudate 123-124 124 [°C.]

TABLE 7 Analytical results of extrudates Formulation 1 Formulation 2Crystallinity None None Lopinavir 102.7% 102.1% Ritonavir  99.4%  99.7%Ritonavir degradation  0.27%  0.36% product Relative amount ritonavir0.272% 0.361% degradation product/ ritonavir Water content  1.3%  0.9%

From the results in Table 5 and Table 7 it is apparent that degradationis more pronounced during extrusion with a screw bearing kneading blocksthan during a run with a screw containing mixing elements.

The higher degradation observed with Formulation 2 relative toFormulation 1 can be attributed to the process parameters. Tohomogeneously mix the higher emulsifier amount into the powder blend,both screw speed and extrusion temperature needed to be increased(Tables 4 and 6). The higher energy input not only led to the desiredhomogeneous extrudate, but also to an increase in degradation. Since anincrease in screw speed usually goes along with some entrapment of airin the extrudate, the vacuum was increased for Formulation 2. Anincreased vacuum in turn increases the energy input, therebycontributing to the enhanced mixing. Another consequence is a lowerwater content of the product.

We claim:
 1. A process for producing a solid dispersion of apharmaceutical active ingredient which comprises feeding thepharmaceutical active ingredient and a matrix-forming agent to anextruder and forming a uniform extrudate, wherein at least 98% by weightof the total amount of active ingredient is present in an amorphousstate: wherein the extruder comprises a housing, and at least tworotating shafts within said housing, wherein each of the shafts carriesa plurality of processing elements disposed axially one behind theother, the processing elements defining (i) a feeding and conveyingsection, (ii) a first mixing section, (iii) an intermediate conveyingsection, (iv) a reverse-flight section, and (v) a discharging section,wherein the processing elements defining the first mixing sectioncomprise at least one mixing element and the processing elementsdefining the reverse-flight section comprise at least one mixing elementand downstream thereto at least one reverse-flight element, wherein theat least one reverse-flight element is based on a screw-type elementhaving a conveying direction opposite to the general conveying directionof the extruder; wherein at least one mixing element is derived from ascrew-type element, has recesses formed in the screw-flight of thescrew-type element, and has a plurality of concentric ring portionsformed by grooves turned into the screw-type element; and wherein theprocessing elements are sized and configured to provide a recurringsequence of pressure build-up that forces the pharmaceutical activeingredient through an annular gap between the extruder housing and ringportions of the mixing element with shearing action and elongation,followed by a reduction in pressure, thereby causing a defined anduniform but not undue stress on the pharmaceutical active ingredient,thereby avoiding high temperatures or high local shear forces that causedecomposition of the pharmaceutical active ingredient and preventingresidues of extruded material from remaining within the extruder overextended periods of time; and wherein said mixing elements enable asufficient degree of mixing or homogenization with less degradation ofthe active ingredient or formulation of other ingredients as compared todegradation of the active ingredient or formulation of other ingredientsresulting from a process employing paddle means or mixing blocks.
 2. Theprocess of claim 1, wherein the processing elements defining thereverse-flight section comprise at least three reverse-flight elementswherein at least one positive-flight screw-type element is arrangedbetween the respective successive reverse-flight elements.
 3. Theprocess of claim 2, wherein the length of the positive-flight screw-typeelement(s) arranged between the second and third reverse-flight elementis in a range from 1 to 15 times the length of the positive-flightscrew-type element(s) arranged between the first and secondreverse-flight elements.
 4. The process of claim 1, wherein theprocessing elements defining the reverse-flight section comprise atleast four reverse-flight elements, wherein at least one positive-flightscrew-type element is arranged between the respective successivereverse-flight elements, and wherein the positive-flight screw-typeelements arranged between successive reverse-flight elements have thesame length.
 5. The process of claim 1, wherein at least onereverse-flight element is positioned downstream to the mixingelement(s).
 6. The process of claim 1, wherein at least one mixingelement does not have a plane surface area with a normal that isparallel and opposite to the general conveying direction.
 7. The processof claim 1, wherein at least one mixing element does not have a facethat is perpendicular to the general conveying direction.
 8. The processof claim 1, wherein at least one mixing element does not have abuttingfaces that are perpendicular to the general conveying direction.
 9. Theprocess of claim 1, wherein at least part of the matrix-forming agent isfed to a hopper of the extruder and at least one component selected from(i) the remainder of the matrix-forming agent, (ii) an activeingredient, (iii) an additive, and (iv) combinations thereof, isintroduced into the extruder through an opening in the extruder barrelat a position upstream of or in a mixing section or reverse-flightsection.
 10. The process of claim 9, wherein the at least one componentis introduced into the extruder at a position at or close to thejunction of the feeding and conveying section and a mixing section orreverse-flight section.
 11. The process of claim 9, wherein the at leastone component is liquid or liquefied.
 12. The process of claim 9,wherein the at least one component comprises a pharmaceuticallyacceptable surfactant.
 13. The process of claim 1, wherein thepharmaceutical active ingredient is dispersed in a polymer in a state ofa solid solution.
 14. The process of claim 1, wherein the matrix-formingagent comprises a pharmaceutically acceptable polymer.
 15. The processof claim 14, wherein the pharmaceutically acceptable polymer is selectedfrom the group consisting of homopolymers of N-vinyl lactams, copolymersof a N-vinyl lactam and one or more comonomers selected fromnitrogen-containing monomers and oxygen-containing monomers, celluloseesters and cellulose ethers, high molecular polyalkylene oxides,polyacrylates and polymethacrylates, oligo- and polysaccharides,poly(hydroxy acids), or mixtures thereof.
 16. The process of claim 1,wherein the matrix-forming agent comprises a member selected frompolyols, waxes and lipids.
 17. The process of claim 1, additionallycomprising feeding at least one additive selected from the groupconsisting of flow regulators, lubricants, fillers, disintegrants,plasticizers, stabilizers or preservatives into the extruder.
 18. Theprocess of claim 1, wherein the extrudate is directly shaped into adosage form.
 19. The process of claim 18, wherein shaping is carried outby calendaring, injection moulding or profile extrusion.
 20. The processof claim 1, additionally comprising grinding the solidified extrudate.21. The process of claim 20, additionally comprising compressing saidsolid dispersion product into a tablet or filling said solid dispersionproduct into a capsule shell
 22. The process of claim 21, additionallycomprising applying a film-coat to the tablet.
 23. The process of claim1, wherein the extruder further comprises a barrel having severalheating zones, wherein the portion of the barrel upstream of the firstreverse-flight element is maintained at a lower temperature than theportion of the barrel downstream of the first reverse-flight element 24.The process of claim 1, wherein the processing elements defining thereverse-flight section comprise at least two reverse-flight elements andat least one positive-flight screw-type element which is arrangedbetween said two reverse-flight elements.
 25. The process of claim 24,wherein said at least two reverse-flight elements have a screw pitchranging from −0.5 times to −1.5 times the screw pitch of the at leaseone positive-flight screw-type elements arranged between the at leasttwo reverse-flight elements.
 26. The process of claim 24, wherein thesaid at least two reverse-flight elements have a screw pitch rangingfrom −0.5 time to −1.5 times the screw pitch of the at least onepositive flight screw-type element arranged between the at least tworeverse-flight elements.
 27. The process of claim 1, wherein the amountof degradation of the active ingredient relative to the amount of activeingredient is less than 0.381%.
 28. A process for producing a soliddispersion of a pharmaceutical active ingredient which comprises feedingthe pharmaceutical active ingredient and a matrix-forming agent to anextruder and forming a uniform extrudate, wherein at least 98% by weightof the total amount of active ingredient is present in an amorphousstate and wherein the amount of degradation of the active ingredientrelative to the amount of active ingredient is less than 0.381%; whereinthe extruder comprises a housing, and at least two rotating shaftswithin said housing, wherein each of the shafts carries a plurality ofprocessing elements disposed axially one behind the other, theprocessing elements defining (i) a feeding and conveying section, (ii) afirst mixing section, (iii) an intermediate conveying section, (iv) areverse-flight section, and (v) a discharging section, wherein theprocessing elements defining the first mixing section comprise at leastone mixing element and the processing elements defining thereverse-flight section comprise at least one mixing element anddownstream thereto at least one reverse-flight element, wherein the atleast one reverse-flight element is based on a screw-type element havinga conveying direction opposite to the general conveying direction of theextruder; wherein at least one mixing element is derived from ascrew-type element, has recesses formed in the screw-flight of thescrew-type element, and has a plurality of concentric ring portionsformed by grooves turned into the screw-type element; and wherein theprocessing elements are sized and configured to provide a recurringsequence of pressure build-up that forces the pharmaceutical activeingredient through an annular gap between the extruder housing and ringportions of the mixing element with shearing action and elongation,followed by a reduction in pressure, thereby causing a defined anduniform but not undue stress on the pharmaceutical active ingredient,thereby avoiding high temperatures or high local shear forces that causedecomposition of the pharmaceutical active ingredient and preventingresidues of extruded material from remaining within the extruder overextended periods of time; and wherein said mixing elements enable asufficient degree of mixing or homogenization with less degradation ofthe active ingredient or formation of other ingredients as compared todegradation of the active ingredient or formation of other ingredientsresulting from a process employing paddle means or mixing blocks.